Syphilis is a chronic, complex sexually transmitted disease caused by the spirochetal bacterium Treponema pallidum. That syphilis remains an alarming global public health problem and is a cofactor for the transmission of HIV underscore the importance of continued studies to elucidate its complex pathogenesis. Such studies are requisite for the development of a syphilis vaccine, an important element of the syphilis eradication initiative. Given that the membrane system of T. pallidum serves as both the physical and functional interface with the host, studies to elucidate the structure, function, and immunology of T. pallidum membrane proteins continue to be essential for the future design of novel syphilis intervention strategies. To this end, the Specific Aims of this proposal are: (1) To refine and implement a new chemotaxis assay for T. pallidum, with emphasis on elucidating potential chemoattractants that may facilitate tissue dissemination by T. pallidum; (2) To assess whether the Mg1B lipoprotein of T. pallidum is a receptor for glucose, the principal carbon and energy source for T. pallidum; (3) To assess the putative role in sensory transduction of Mcp1 and three other methyl-accepting chemotaxis proteins of T. pallidum; (4) To implement a new combined genome- and invasin-based strategy to identify T. pallidum rare outer membrane proteins that may qualify as syphilis vaccine candidates; and (5) To continue to investigate mechanisms by which T. pallidum and its proinflammatory lipoproteins facilitate HIV transmission, with emphasis on examining the upregulation of CCR5, the HIV-1 coreceptor, on T. pallidum-activated immune cells. The pursuit of these aims will further our understanding of T. pallidum membrane biology relevant to syphilis pathogenesis, tissue dissemination, and vaccine development, as well as delineate the molecular constituents which induce salient inflammatory processes that culminate in clinical disease. The aims also seek to advance new strategies for utilizing surrogate genetic systems for T. pallidum, such as E. coli and T. denticola, as a means of elucidating the interrelationship between T. pallidum membrane biology and syphilis pathogenesis.